Recent studies have linked the dysbindin gene to the complex neurological disorder of schizophrenia. In non-neuronal cells, dysbindin is responsible for Hermansky-Pudlak Syndrome, a disease characterized by defects in pigmentation and blood clotting, and dysbindin is possibly involved in Duchenne's Muscular Dystrophy. Dysbindin is expressed in the brain, although, little is known about the function of dysbindin in neurons. A reduction in dysbindin mRNA and protein has been reported in brains of schizophrenic patients suggesting that dysbindin has an important neuronal function. Several lines of evidence suggest that dysbindin may affect synaptic transmission. First, over-expression and RNA interference studies in cortical neurons suggest that dysbindin promotes transmitter release and affects the expression of synaptic proteins. Second, dysbindin staining has been reported at the synapse by immunohistochemistry. Third, dysbindin co-fractionates with synaptic proteins. Fourth, dysbindin interacts with snapin, a protein implicated in the modulation of synaptic vesicle release. Our primary objective is to test the hypothesis that dysbindin functionally affects synaptic transmission. We take advantage of a readily-available loss-of-function animal model, sandy, which is a functional null of dysbindin. Aim 1: Using electrophysiological tests we will identify any defects in synaptic physiology at the well-studied hippocampal CA3-CA1 connection in homozygous sandy mutants (Sdy -/-). Aim 2: Using Western Blot analysis, I will identify whether the loss of dysbindin in the sandy mice leads to a reduction in hippocampal proteins that participate in synaptic transmission. The identification of any alterations in these synaptic proteins may provide a molecular explanation for potential synaptic dysfunction. Aim 3: Using immunofluorescence in hippocapal cell culture, I will use newly generated polyclonal antibodies against dysbindin to evaluate the extent to which dysbindin is present in pre-synaptic and/or post-synaptic compartments. This investigation is consistent with the mission of the NIH encouraging discoveries in the basic science to better define the pathophysiology of disease. Understanding the function of dysbindin in neurons has direct relevance to public health as it might contribute to an understanding of the pathophysiology of schizophrenia. In lay language, understanding the basic function of the dysbindin protein may contribute to an explanation for the cause of schizophrenia.